A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.

The BCL6 transcriptional repressor is required for the development of germinal center (GC) B cells and diffuse large B cell lymphomas (DLBCLs). Although BCL6 can recruit multiple corepressors, its transcriptional repression mechanism of action in normal and malignant B cells is unknown. We find that in B cells, BCL6 mostly functions through two independent mechanisms that are collectively essential to GC formation and DLBCL, both mediated through its N-terminal BTB domain. These are (1) the formation of a unique ternary BCOR-SMRT complex at promoters, with each corepressor binding to symmetrical sites on BCL6 homodimers linked to specific epigenetic chromatin features, and (2) the "toggling" of active enhancers to a poised but not erased conformation through SMRT-dependent H3K27 deacetylation, which is mediated by HDAC3 and opposed by p300 histone acetyltransferase. Dynamic toggling of enhancers provides a basis for B cells to undergo rapid transcriptional and phenotypic changes in response to signaling or environmental cues.

• Publication year

  2013

• Venue

  Cell Reports

• Publication date

  2013-08-15

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.celrep.2013.06.016PMID 23911289PMCID PMC3854650
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Active enhancers can be toggled to a poised but not erased state through SMRT-dependent H3K27 deacetylation, with HDAC3 promoting and p300 histone acetyltransferase opposing this transition.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• A unique ternary BCOR-SMRT complex forms at promoters, with each corepressor binding symmetrical sites on BCL6 homodimers linked to specific epigenetic chromatin features.

  Confidence 0.94

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• BCL6 functions in B cells through two independent BTB-domain-mediated mechanisms that are collectively essential for germinal center formation and diffuse large B cell lymphoma.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review

• active enhancers

  genomic region

  Enhancer elements that are the substrate for state toggling in the mechanism described here.

  Aliases: enhancers

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• bcl6 transcriptional repressor

  protein, transcription factor

  A transcriptional repressor protein studied here for its role in B cells and lymphoma.

  Aliases: BCL6

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• bcor-smrt complex

  protein complex

  A promoter-associated ternary complex formed by BCOR and SMRT with BCL6 in the model described here.

  Aliases: BCOR/SMRT complex

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• btb domain

  protein domain

  The N-terminal protein domain of BCL6 that mediates the mechanisms described in this abstract.

  Aliases: POZ domain

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• diffuse large b cell lymphomas

  disease, cancer type

  An aggressive B cell lymphoma context in which BCL6 activity is examined.

  Aliases: DLBCLs

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• epigenetic chromatin features

  molecular feature, epigenetic mark

  Chromatin marks and states associated with where BCL6-linked repression complexes localize.

  Aliases: chromatin features

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• germinal center b cells

  cell type, immune cell type

  B cells in the germinal center state used as the normal developmental context in this study.

  Aliases: GC B cells

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• h3k27 deacetylation

  histone modification, chromatin modification

  Removal of acetyl groups from histone H3 lysine 27 as part of enhancer state control.

  Aliases: H3K27Ac removal

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• hdac3

  enzyme, histone deacetylase

  A histone deacetylase that mediates the SMRT-dependent deacetylation step described here.

  Aliases: histone deacetylase 3

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• p300 histone acetyltransferase

  enzyme, histone acetyltransferase

  A histone acetyltransferase that opposes the deacetylation-driven enhancer transition described here.

  Aliases: EP300, p300

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• promoters

  genomic region

  Gene regulatory regions near transcription start sites where the described repressor complex assembles.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• smrt

  protein, corepressor

  A corepressor that participates in BCL6-associated repression and enhancer regulation in this abstract.

  Aliases: NCOR2

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review

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